Sildenafil, alone and in combination with imipramine, display antidepressant-like effects in a time-dependent sensitisation-induced (TDS) rat model of treatment-resistant depression

Abstract

Background: Despite numerous pharmacotherapies at our disposal to treat major depressive disorder (MDD), extremely high rates of treatment resistance prevail, while burdensome side effects are common. To address these challenges and improve treatment outcomes, there is an urgent need for novel, improved and better-tolerated pharmacological options. Evidence suggests that targeting mood-modulating biochemical systems other than the monoaminergic system is essential, offering promising alternatives. In this regard, pathophysiological features of MDD, including hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, impaired neuroplasticity, neuroinflammation, immune dysfunction and oxidative stress, represent targets of interest. The selective phosphodiesterase type 5 (PDE5) inhibitor, sildenafil, is one such potential candidate, with pre-clinical data suggesting it has antidepressant-like properties. Although speculative, these actions may involve altered neuroplasticity, and anti-inflammatory and antioxidant actions. However, its therapeutic potential in treatment resistant depression (TRD) has not been explored. Aim: To investigate whether sildenafil, either as a monotherapy or as augmentation with a traditional antidepressant, can exert antidepressant-like bio-behavioural effects in a rodent model of TRD, and whether such actions involve the above-mentioned processes. Methods: A time-dependent sensitisation-induced (TDS-induced) model of TRD in Flinders Sensitive Line (FSL) male rats was used. TDS-naïve groups were left undisturbed from postnatal day 40 (PND40) to PND54, whereas TDS-exposed groups were subjected to a TDS paradigm from postnatal day PND40. Starting on PND55, rats received either vehicle control (VEH), imipramine (15 mg/kg/day) (IMI-15), sildenafil (3 mg/kg/day) (SIL-3), sildenafil (10 mg/kg/day) (SIL-10) or IMI-15 + SIL-3 for 10 days. The open field test (OFT) and forced swim test (FST) were performed on PND62 and PND63, respectively. Hippocampal brain-derived neurotrophic factor (BDNF), serotonin (5-HT), norepinephrine (NE), glutathione (GSH), and glutathione disulphide (GSSG) levels were assayed on PND65. Results: TDS exposure elevated immobility time in FSL rats (depressive-like behaviour) in the FST (p = 0,0186) compared to stress-naïve FSL rats. Sub-chronic IMI-15 treatment decreased immobility in TDS-compared to VEH-treated TDS-exposed rats (p = 0,0097), hence inducing a treatment response in TDS rats. SIL-10 (p = 0,0196), and IMI-15 + SIL-3 (p = 0,0005) were similarly effective while SIL-3 was not. Importantly, SI L-3 augmented the antidepressant-like effects of IMI-15, with IMI-15 + SIL-3 displaying greater immobility-reducing capability compared to IMI-15 in TDS-exposed rats. Moreover, TDS exposure elevated hippocampal BDNF (p = 0,0007), 5-HT (p < 0,0001), NE (p = 0,0227), GSH (p < 0,0001), and GSSG (p = 0,0185) levels in FSL rats compared to non-stressed FSL rats. IMI-15 (p = 0,0317) and SIL-10 (p = 0,0078) reduced hippocampal BDNF levels in TDS-exposed rats but did not influence hippocampal 5-HT, NE, GSH, and GSSG levels compared to VEH. In addition, compared to VEH, sub-chronic SIL-3 treatment reduced hippocampal GSH (p = 0,0018) levels of TDS-exposed rats without altering hippocampal BDNF, 5-HT, NE, and GSSG levels. Sub-chronic IMI-15 + SIL-3 treatment reduced hippocampal BDNF (p = 0,0024), 5-HT (p = 0,0115), GSH (p < 0,0001), and GSSG (p = 0,0002) levels of TDS-exposed rats compared to VEH, but without affecting hippocampal NE levels. SIL-3 augmented the 5-HT-(p = 0,0115) and GSSG-lowering (p = 0,0002) effects of IMI-15, with IMI-15 + SIL-3 reaching statistical significance in TDS-exposed rats but not IMI-15 or SIL-3 alone. Finally, SIL-3 augmented the GSH-reducing action of IMI-15 (p = < 0,0001) compared to SIL-3 alone (p = 0,0018), whereas IMI-15 by itself had no such effects in TDS-exposed rats. Conclusion: TD S + FSL rats displayed depressive-like behaviour and evidence for oxidative stress but paradoxically with elevated hippocampal monoamines and BDNF. This apparent counterregulatory action of BDNF is reaffirmed by IMI-15, SIL-10, and IMI-15 + SIL-3 reversing elevated BDNF and depressive-like behaviour in TDS + FSL rats. Also, SIL-3 only reversed some redox changes, whereas IMI-15 + SIL-3 reversed serotonergic and all redox changes. SIL-3 augments the antidepressant-like effects of IMI-15 in TDS-exposed rats.